Current approaches to cancer chemotherapy and other immunological therapies focus on the use of cell-specific therapeutic agents. Ideally, immunotoxins should discriminate to a high degree between target and non-target cells. The present invention discloses an immmunotoxin conjugate formed between monoclonal antibody OVB-3 (which specifically binds to human ovarian cancer cells) and Pseudomonas exotoxin.
Since the advent of the monoclonal antibody methodology disclosed in Koprowski et al (U.S. Pat. No. 4,172,124) many monoclonal antibodies designed to treat a wide variety of human ailments have been developed. However, two problems have prevented this methodolgy from being practiced more extensively. First, many monoclonal antibodies to hmman target (e.g. cancer) cells also bind to non-target (normal) human cells. Secondly, many of the toxin delivery systems reduce the effectiveness of the toxin, reduce the entry capacity of the toxin into the target cell, or are not specific enough to deliver a sufficent amount of toxin to the target site. The present invention discloses an immunotoxin which differentiates between normal and cancerous cells, is highly specific for human ovarian cancer cells, and is capable of carrying and delivering a toxin to the cancer cell without destroying the toxin's entry and lethal activity. In this manner, the present invention satisfies a long felt need in the area of cancer chemotherapy: very few ovarian cancer monoclonal antibodies exist, and those that do are not capable of delivering an exotoxin in condition for the cancer cell to internalize the endotoxin. Furthermore, the present invention uses recently developed technology to produce an effective immunotoxin which specifically binds to ovarian cancer cells without binding to normal human cells.
The present invention builds on the discovery disclosed by the same inventors in U.S. Pat. No. 4,545,985, titled "Pseudomonas Exotoxin Conjugate Immunotoxins." This patent is hereby incorporated by reference because it discloses the method used in the present invention for modifying Pseudomonas exotoxin so that the toxin will selectively kill target human tumor cells.
The present invention is an improvement on this process; with the production of highly specific monoclonal antibodies, human ovarian cancer may be targeted and treated by the products of this invention.
Pseudomonas exotoxin (PE) has been conjugated to a variety of monoclonal antibodies recognizing certain human tumors and to a monoclonal antibody recognizing the human y antigen blood group substance [Richert et al, J. Biol. Chem., 258:8902-8907 (1983); and Fredman et al, J. Biol. Chem., 258:11206-11210 (1983)]. The toxin conjugates specifically kill the appropriate target cells. PE can now be conjugated to a variety of peptides, proteins, and growth factors that react with specific receptors on cells. These include sarcoma growth factors, melanocyte stimulating hormone (MSH) somatostatin, glucagon, insulin, transferrin, low density lipoprotein, calcitonin, alpha.sub.2 -macroglobulin, and lysine-bradykinin. Pseudomonas exotoxin is particularly preferable to other toxins (such as ricin or diphtheria toxin) because large amounts are easily prepared, because humans do not usually have neutralizing antibodies against it (as is the case with diphtheria toxin), and because it does not need to be separated into subunits before being conjugated (as does ricin toxin).